Background and purpose
The aim of this study was to examine non‐motor symptoms in different Parkinson's disease (PD) motor subtypes and their associations with quality of life (QoL).
Methods
A total ...of 132 patients with early PD with comprehensive motor examinations and non‐motor symptom assessments were included. Motor subtypes were classified based on Stebbins’ method. Non‐motor symptoms were assessed by the Non‐Motor Symptom Scale (NMSS) and validated by more comprehensive instruments, including the Pittsburgh Sleep Quality Index (PSQI) and Fatigue Severity Scale (FSS). QoL was measured by the Parkinson's Disease Questionnaire‐8.
Results
We identified 66 patients (50%) with tremor‐dominant (TD) subtype, 47 (35.6%) with postural instability and gait disorder (PIGD) subtype and 19 (14.4%) with Intermediate subtype. By comparing NMSS scores, patients with the PIGD subtype had more severe sleep impairment and fatigue (domain 2 score: 5.64 vs. 2.52, P < 0.001), urinary symptoms (domain 7 score: 6.96 vs. 3.48, P = 0.005) and overall more severe non‐motor symptoms (NMSS total score: 25.89 vs. 17.27, P = 0.031), compared with patients with the TD subtype. Validation using the PSQI and FSS again suggested that patients with the PIGD subtype had independently and significantly more severe sleep impairment (PSQI score: 5.57 vs. 4.29, P = 0.020) and fatigue (FSS score: 34.81 vs. 25.85, P = 0.003) compared with patients with the TD subtype. Several non‐motor symptoms had significant associations with QoL, among which sleep impairment and fatigue (P < 0.0001, partial r2 = 0.273) explained the largest proportion of QoL variability in patients with PD.
Conclusions
Patients with the PIGD subtype had more severe sleep impairment, fatigue and urinary disturbance compared with patients with the TD subtype. Sleep impairment and fatigue were the most important factors affecting QoL independent of motor subtypes. Prompt identification and treatment of these non‐motor symptoms may improve patients’ QoL.
Abstract
STUDY QUESTION
Are higher overall and central adiposity associated with reduced fecundability, measured by time-to-pregnancy (TTP), in Asian women?
SUMMARY ANSWER
Higher overall adiposity, ...but not central adiposity, was associated with longer TTP in Asian women.
WHAT IS KNOWN ALREADY
High body mass index (BMI) has been associated with a longer TTP, although the associations of body composition and distribution with TTP are less clear. There are no previous studies of TTP in Asian women, who have a relatively higher percentage of body fat and abdominal fat at relatively lower BMI.
STUDY DESIGN, SIZE, DURATION
Prospective preconception cohort using data from 477 Asian (Chinese, Malay and Indian) women who were planning to conceive and enrolled in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) study, 2015-2017.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Women's mean age was 30.7 years. Overall adiposity was assessed by BMI, sum of 4-site skinfold thicknesses (SFT) and total body fat percentage (TBF%, measured using air displacement plethysmography); central adiposity was assessed by waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and A body Shape Index (ABSI). Pregnancy occurring within one year from recruitment was ascertained by ultrasonography. Those who did not conceive within one year of recruitment, were lost to follow-up, or initiated fertility treatment were censored. TTP was measured in cycles. Discrete-time proportional hazards models were used to estimate the fecundability ratio (FR) and 95% confidence interval (CI) for each anthropometric measure in association with fecundability, adjusting for confounders.
MAIN RESULTS AND THE ROLE OF CHANCE
Compared to women with a normal BMI of 18.5-22.9 kg/m2, women with higher BMI of 23-27.4 and ≥27.5 kg/m2 showed lower FR of 0.66 (95% CI 0.45, 0.97) and 0.53 (0.31, 0.89), respectively. Compared to women in the lowest quartile of SFT (25-52.9 mm), those in the highest quartile of ≥90.1 mm showed lower FR of 0.58 (95% CI 0.36, 0.95). Compared to women in the lowest quartile of TBF% (13.6-27.2%), those in the upper two quartiles of 33.0-39.7% and ≥39.8% showed lower FR of 0.56 (95% CI 0.32, 0.98) and 0.43 (0.24, 0.80), respectively. Association of high BMI with reduced fecundability was particularly evident among nulliparous women. Measures of central adiposity (WC, WHR, WHtR, ABSI) were not associated with fecundability.
LIMITATIONS REASONS FOR CAUTION
Small sample size could restrict power of analysis.The analysis was confined to planned pregnancies, which could limit generalizability of findings to non-planned pregnancies, estimated at around 44% in Singapore. Information on the date of last menstrual period for each month was not available, hence the accuracy of self-reported menstrual cycle length could not be validated, potentially introducing error into TTP estimation. Measures of exposures and covariates such as cycle length were not performed repeatedly over time; cycle length might have changed during the period before getting pregnant.
WIDER IMPLICATIONS OF THE FINDINGS
Other than using BMI as the surrogate measure of body fat, we provide additional evidence showing that higher amounts of subcutaneous fat that based on the measure of SFT at the sites of biceps, triceps, suprailiac and subscapular, and TBF% are associated with longer TTP. Achieving optimal weight and reducing total percentage body fat may be a potential intervention target to improve female fertility. The null results observed between central adiposity and TTP requires confirmation in further studies.
STUDY FUNDING/COMPETING INTEREST(S)
This research is supported by Singapore National Research Foundation under its Translational and Clinical Research Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council, (NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014). Additional funding is provided by the Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore. Y.S.C., K.M.G., F.Y. and Y.S.L. have received reimbursement to speak at conferences sponsored by companies selling nutritional products. Y.S.C., K.M.G. and S.Y.C. are part of an academic consortium that has received research funding from Abbott, Nutrition, Nestle and Danone. Other authors declared no conflicts of interest.
TRIAL REGISTRATION NUMBER
N/A.
Background and purpose
This study quantified the total brain and periventricular white matter hyperintensity (WMH) burdens in patients with early Parkinson’s disease (PD) and explored their ...associations with cardiovascular risk factors and cognitive performance.
Methods
A total of 175 non‐demented patients with early PD who had undergone baseline brain magnetic resonance imaging were included. Comprehensive neurocognitive testing was conducted to identify PD with mild cognitive impairment (PD‐MCI) and to evaluate performances in individual cognitive domains. Cardiovascular risk was expressed as a modified Framingham 10‐year cardiovascular risk score (mFRS).
Results
A total of 53.7% of this early PD cohort fulfilled the diagnostic criteria for PD‐MCI. An increase in mFRS was significantly associated with increases in the total brain WMH (P = 0.015) and periventricular WMH (P = 0.040) burden, independent of age and gender. The periventricular WMH burden was significantly associated with PD‐MCI (P = 0.046) in early PD, independent of cardiovascular risk factors. Patients in the 5th quintile of periventricular WMH burden were 8.6 times more likely to have PD‐MCI compared with patients in the 1st quintile of periventricular WMH burden (P = 0.004). However, total brain WMH burden was not associated with PD‐MCI (P = 0.158). In individual cognitive domains, heavier periventricular WMH burden was associated with worse executive function and visuospatial function independent of cardiovascular risk factors.
Conclusion
Periventricular WMHs are a useful imaging biomarker for cognitive impairment in early PD. Cardiovascular risk factors, although associated with periventricular WMHs, were unable to fully explain the association between periventricular WMHs and cognitive impairment in early PD.
There are considerable challenges in directly targeting the mutant p53 protein, given the large heterogeneity of p53 mutations in the clinic. An alternative approach is to exploit the altered fitness ...of cells imposed by loss-of-wild-type p53. Here we identify niclosamide through a HTS screen for compounds selectively killing p53-deficient cells. Niclosamide impairs the growth of p53-deficient cells and of p53 mutant patient-derived ovarian xenografts. Metabolome profiling reveals that niclosamide induces mitochondrial uncoupling, which renders mutant p53 cells susceptible to mitochondrial-dependent apoptosis through preferential accumulation of arachidonic acid (AA), and represents a first-in-class inhibitor of p53 mutant tumors. Wild-type p53 evades the cytotoxicity by promoting the transcriptional induction of two key lipid oxygenation genes, ALOX5 and ALOX12B, which catalyzes the dioxygenation and breakdown of AA. Therefore, we propose a new paradigm for targeting cancers defective in the p53 pathway, by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling.
The accurate prediction of physicochemical properties of condensed systems is a longstanding goal of theoretical (quantum) chemistry. Ionic liquids comprising entirely of ions provide a unique ...challenge in this respect due to the diverse chemical nature of available ions and the complex interplay of intermolecular interactions among them, thus resulting in the wide variability of physicochemical properties, such as thermodynamic, transport, and spectroscopic properties. It is well understood that intermolecular forces are directly linked to physicochemical properties of condensed systems, and therefore, an understanding of this relationship would greatly aid in the design and synthesis of functionalized materials with tailored properties for an application at hand. This review aims to give an overview of how electronic structure properties obtained from quantum chemical methods such as interaction/binding energy and its fundamental components, dipole moment, polarizability, and orbital energies, can help shed light on the energetic, physical, and spectroscopic properties of semi-Coulomb systems such as ionic liquids. Particular emphasis is given to the prediction of their thermodynamic, transport, spectroscopic, and solubilizing properties.
Macrophages are specialized phagocytic cells, present in all tissues, which engulf and digest pathogens, infected and dying cells, and debris, and can recruit and regulate other immune cells and the ...inflammatory response and aid in tissue repair. Macrophage subpopulations play distinct roles in these processes and in disease, and are typically recognized by differences in marker expression, immune function, or tissue of residency. Although macrophage subpopulations in the brain have been found to have distinct developmental origins, the extent to which development contributes to macrophage diversity between tissues and within tissues is not well understood. Here, we investigate the development and maintenance of mouse lung macrophages by marker expression patterns, genetic lineage tracing and parabiosis. We show that macrophages populate the lung in three developmental waves, each giving rise to a distinct lineage. These lineages express different markers, reside in different locations, renew in different ways, and show little or no interconversion. Thus, development contributes significantly to lung macrophage diversity and targets each lineage to a different anatomical domain.
Summary
Background
Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral ...cutaneous melanoma (NAM) in Asians are not well understood.
Objectives
To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma.
Methods
We performed comprehensive genomic profiling of 409 cancer‐associated genes, using next‐generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs.
Results
Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild‐type (triple‐WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell‐cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell‐cycle aberrations were independent prognostic factors of melanoma‐specific survival.
Conclusions
This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians.
What's already known about this topic?
Mutation frequencies of driver genes vary between melanoma subtypes.
Acral melanoma is the most common subtype of melanoma in Asians.
KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype
What does this study add?
NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment.
Melanomas with cell‐cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration.
What is the translational message?
Cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival.
These observations should be explored further for future drug development.
Linked Comment: Johansson. Br J Dermatol 2020; 182:1085.
Plain language summary available online
Microencapsulation is a fundamental concept behind a wide range of daily applications ranging from paints, adhesives, and pesticides to targeted drug delivery, transport of vaccines, and self-healing ...concretes. The beauty of microfluidics to generate microcapsules arises from the capability of fabricating monodisperse and micrometer-scale droplets, which can lead to microcapsules/particles with fine-tuned control over size, shape, and hierarchical structure, as well as high reproducibility, efficient material usage, and high-throughput manipulation. The introduction of supramolecular chemistry, such as host–guest interactions, endows the resultant microcapsules with stimuli-responsiveness and self-adjusting capabilities, and facilitates hierarchical microstructures with tunable stability and porosity, leading to the maturity of current microencapsulation industry. Supramolecular architectures and materials have attracted immense attention over the past decade, as they open the possibility to obtain a large variety of aesthetically pleasing structures, with myriad applications in biomedicine, energy, sensing, catalysis, and biomimicry, on account of the inherent reversible and adaptive nature of supramolecular interactions. As a subset of supramolecular interactions, host–guest molecular recognition involves the formation of inclusion complexes between two or more moieties, with specific three-dimensional structures and spatial arrangements, in a highly controllable and cooperative manner. Such highly selective, strong yet dynamic interactions could be exploited as an alternative methodology for programmable and controllable engineering of supramolecular architectures and materials, exploiting reversible interactions between complementary components. Through the engineering of molecular structures, assemblies can be readily functionalized based on host–guest interactions, with desirable physicochemical characteristics. In this Account, we summarize the current state of development in the field of monodisperse supramolecular microcapsules, fabricated through the integration of traditional microfluidic techniques and interfacial host–guest chemistry, specifically cucurbitnuril (CBn)-mediated host–guest interactions. Three different strategies, colloidal particle-driven assembly, interfacial condensation-driven assembly and electrostatic interaction-driven assembly, are classified and discussed in detail, presenting the methodology involved in each microcapsule formation process. We highlight the state-of-the-art in design and control over structural complexity with desirable functionality, as well as promising applications, such as cargo delivery stemming from the assembled microcapsules. On account of its dynamic nature, the CBn-mediated host–guest complexation has demonstrated efficient response toward various external stimuli such as UV light, pH change, redox chemistry, and competitive guests. Herein, we also demonstrate different microcapsule modalities, which are engineered with CBn host–guest chemistry and also can be disrupted with the aid of external stimuli, for triggered release of payloads. In addition to the overview of recent achievements and current limitations of these microcapsules, we finally summarize several perspectives on tunable cargo loading and triggered release, directions, and challenges for this technology, as well as possible strategies for further improvement, which will lead to substainitial progress of host–guest chemistry in supramolecular architectures and materials.
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